The present invention relates to medicine, and more specifically to pharmacology, veterinary, cosmetology, and in particular to synthetic biological active compound of heterocycle series, which possess antimicrobial, antiviral, antichlamydia and immune stimulating activities: derivatives of 5-oxo-5H-[1]-benzopyrano-[5,6-b]-4-oxo-4H-[1,2]-pyrimido-1,4,5,6-tetrahydr o-1,3-thiazine. The derivatives mentioned above have high antimicrobial activity to various mycobacteria, substantial antiviral activity relative to Herpes simplex virus, high antichlamydial activity, and also activity as inducers of interferon. The substances compounds are intended, mainly, for the use in medical practice for treating tuberculosis, mycobacteriosis, viral diseases, infections caused by chlamydia, and also diseases which are accompanied by immunodeficiency, in particular malignant neoplasm. In addition, the above mentioned compound can be used for the same purposes in veterinary and cosmetology.
As known, there are many unsolved problems in modern chemotherapy of infectious diseases. Among bacterial infections one of the most serious problems is caused by tuberculosis, whose treatment is especially complicated due to high resistivity of tuberculosis mycobacteria to the action of chemotherapeutical agents [1]. Moreover, existing compounds possess substantial disadvantage-wide spread of mycobacteria which are resistant to them.
Historically first antituberculosis compounds were derivatives of phenols, benzioc acids (2), mercaptobenzimidizols (3), p-aminosalicyclic acid (4). The most active antituberculosis agents were derivatives of isonicotine acid discovered at the end of 40.sup.s of our century, such as isoniazide and its analogs, which are used at present, ethionamide, ethambutole, aminoglycosides, rifampicin, fluoroquinols (1). During therapy of tuberculosis and mycobateriosis usually 2-3 compounds are simultaneously prescribed, which slow appearance of resistant forms of mycobacteria, but do not solve the problems of getting used and resistance completely. Therefore search for new active antituberculosis agents, including those which act on forms of mycobacteria which are resistant to isoniazide, is still actual. Viral diseases pose for modern medicine problems which are not less serious. As a rule, viral infections, such as those caused by viruses of herpes group, are very difficult to be treated, which is connected with insufficient efficiency of existing compounds as well as fast changes of viruses, whose mutations cause appearance of resistant forms (5-7). Synthetic compounds for treatment of diseases caused by viruses of herpes group include acylovir, gancyclovir, retrovir (5) and others whose efficiency is not always sufficient.
Many problems exist during treatment of diseases caused by chlamydia, including widely spread urogenital infections (8). Chlamydia of which are intracellular parasites, are little accessible for the majority of existing compounds and, in addition to this, widespread resistance to the latter caused an appearance of a great number of chronic forms of diseases. To treat chlamydia infections, usually there are used compounds of tetracycline series, macrolids and fluoroquinolones, for example ciprophoxacin (8).
Frequently diseases of viral and bacterial nature occur on the background of reduction of activity of organism immune system, and therefore the problem of development of efficient compounds for treatment of immune deficient states of various origin is also one of the most actual problems. In addition, stimulation of activity of immune system contributes to fight of organism against tumoral processes during which multiple resistance to existing treatment compounds is observed (9).
It is necessary to note that at present intense search of biologically active compounds among derivatives of pyrimidine series is conducted. In particular, in the pyrimidine series a lot of derivatives are known which are used as medicinal compounds (10). Monocyclic derivatives of pyrimidine, in particular barbituric acids possess universal antibacterial action because of antagonism with pyrimidine basis of DNA (11). Active bactericidal compounds are found between hydrazine derivatives of pyrimidine, thyopyrimidines (14), alkoxy-and aminopyrimidines (15). Ethers of pyrimidinecarboxylic acids exhibit antitumor activity (16). Many derivatives of barbituric acids possess substantial antiviral activity (13,17). Derivatives [4,2-b] of pyrimidopyran possess anti-inflammatory properties (18). The same action is found in many N-aryl and N-cyclohexyl-barbituric acid (19). All examples presented hereinabove are united by common chemical structure, since they are monocyclic derivatives of pyrimidine (containing one pyrimidine heterocycle, not conjugated with other cycling systems).
An example of finding biological properties in three cyclic derivatives of pyrimidine row is known, but their action is limited by anti-allergic activity (20) and is not extended to the area of antimicrobial and antiviral action. Derivatives of 2,4-[1H, 3H, 5H]-[1] benzopyrano [2,3-d]-pyrimidine patented as anti-allergic agents are the closest to the claimed compounds as to chemical structure (20).
As a prototype, there is selected hydrazide of izonicotinic acid (isoniazide) (9). The selection is based on its coincidence with the claimed substance as to important objective: anti-tuberculosis action. Izoniazide is one of the most efficient anti-tuberculosis compounds, it can be used in any medicinal forms (pills, injections, inhalations), and at the same time the object of the invention and the prototype belong to the class of nitrogen heterocycles as to their chemical structure.